Cyclosporin A (CsA,
Sandimmune) is known to reverse
P-glycoprotein (P-gp170)-mediated multidrug resistance as efficiently as other prototype compounds of resistance modifiers. The immunosuppressive activity and nephrotoxicity of CsA, however, may limit its clinical use.
PSC-833, a new
cyclosporine, exerts a similar resistance-modifying activity but lacks toxicity or immunosuppressive activity. We have tested its potency in vitro and in vivo on the
L1210 leukemia cell line transfected with a full-length
cDNA copy of the human mdr I gene, which showed a stable 30-fold resistance towards
adriamycin as compared to the parental cell line. In vitro growth of the transfected cell was unchanged. In vivo growth was less aggressive; the survival time of inoculated mice was prolonged. In vitro,
PSC-833 was at least as potent as CsA or
verapamil in reversing multidrug resistance. In vivo, the
drug-resistant
L1210 leukemia was completely unresponsive to i.v. monotherapy with
adriamycin at its maximum tolerated dose (MTD).
PSC-833 enhanced the activity and toxicity of
adriamycin. The MTD of
adriamycin was about 3 times lower than when given alone. On this basis, the MTD of i.v.
adriamycin in combination with oral
PSC-833 successfully overcame refractoriness to treatment. Survival times of the mice were considerably prolonged and even some cures of leukemic mice occurred.